One in ten adults will have diabetes by 2040. Both type 1 (T1D) and type 2 diabetes (T2D) are characterized by a reduction in functional ?-cell mass. Our overarching hypothesis is that a precise understanding of the molecular mechanisms controlling human ?-cell proliferation may provide novel strategies to 1.) expand functional ?-cell mass prior to islet transplantation in T1D; and 2.) prevent or delay the development of T2D in individuals at risk. The specific objective of this project is to elucidate the role of heparin-binding EGF-like growth factor (HB-EGF) in the control of ?-cell proliferation. Previous findings and recent data from our group provide a strong basis for this proposal and include: 1.) HB-EGF is a potent human ?-cell mitogen; 2.) HB-EGF expression in human islets correlates with Body Mass Index; 3.) ?-cell proliferation in response to glucose and other ?-cell mitogens is blocked by inhibition of HB-EGF or EGF receptor (EGFR) signaling; 4.) somatostatin (SST) blocks HB-EGF-induced ?-cell proliferation. These data led us to formulate the hypothesis that autocrine/paracrine HB-EGF signaling through EGFR in ?-cells integrates positive and negative signals to regulate ?-cell proliferation. This hypothesis will be tested by: 1.) Investigating whether glucose and other mitogens promote ?-cell proliferation via HB-EGF-dependent EGFR activation in isolated rodent and human islets. Then the mechanism involved in metalloproteinase-dependent shedding of HB-EGF from its membrane-bound precursor will be determined using genetic and pharmacological approaches. 2.) Elucidating the mechanisms by which SST and other inhibitory G protein-coupled receptors (GPCR) dampen glucose-induced EGFR signaling in isolated rodent and human islets. In particular, whether this is mediated by direct interaction between inhibitory GPCRs and the EGFR will be investigated in collaboration with M. Bouvier at the Institut de Recherche en Immunologie et Cancrologie. 3.) Ascertaining the role of HB-EGF in ?-cell compensation using a conditional ?-cell specific knockout approach in mice in response to high-fat feeding and gestation. The importance of HB-EGF for human ?-cell proliferation will be confirmed by transplanting HB-EGF-deficient juvenile human islets into exendin-4-treated immunodeficient mice, a model established by our collaborator A. Powers at Vanderbilt University. Dissecting the mode of regulation and mechanism of action of HB-EGF will provide important insights into the regulation of ?-cell proliferation. From a therapeutic perspective, these findings may help design novel strategies to expand ?-cell mass prior to islet transplantation in T1D and to maintain or expand functional ?-cell mass in T2D.